1. Field of the Invention
The present invention relates to a novel synthesis of (−)-galantamine and N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-5-hydroxy-4-methoxy benzene carboxamide, which is a key intermediate for the synthesis of (−)-galantamine, a drug approved for Alzheimer disease.
2. Description of the Related Art
N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2) is an important intermediate for (−)-galantamine synthesis. See, e.g., the following references:    (1) Kametani, T.; Yamaki, K.; Yagi, H.; Fukumoto, K. J. Chem. Soc., Chem. Commun. 1969, 425.    (2) Kametani, T.; Yamaki, K.; Yagi, H.; Fukumoto, K. J. Chem. Soc. (C) 1969, 2602.    (3) Kametani, T.; Shishido, K.; Hayashi, E.; Seino, C.; Kohno, T.; Shibuya, S.; Fukumoto, K. J. Org. Chem. 1971, 36, 1295.    (4) Kametani, T.; Yamaki, K.; Terui, T. J. Heterocycl. Chem. 1973, 10, 35.    (5) Kametani, T.; Premila, M. S.; Fukumoto, K. Heterocycles 1976, 4, 111.    (6) José Marco-Contelles, Maria do Carmo Carreiras, Carolina Rodríguez, Mercedes Villarroya, and Antonio G. García; Chem. Rev. 2006, 106, 116-133.
The entire content of each of the above references is incorporated herein by reference.
The general processes disclosed in the art for the preparation of N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2) is based on coupling 2-bromo-5-benzyloxy-4-methoxy benzoic acid (B4) and N-methyl-N-2-(4-benzyloxyphenyl)ethyl amine (A3) followed by de-protection of the benzyl ether with hydrobromic acid. (see Kametani, et. al., J. Chem. Soc. (C) 1969, 2602). As shown in Scheme I, there are nine steps in the synthesis of the title compound.

Specifically, the nine steps as shown in Scheme I are:
1) Tyramine is formulated with a mixture of ethyl formate and formic acid in THF to give amide A1.
2) Amide A1 is benzylated with benzyl bromide and potassium carbonate in DMF to obtain compound A2.
3) Compound A2 is reduced by lithium aluminum hydride in THF to give amine A3.
4) Bromination of 3,4-dimethoxybenzaldehyde using bromine in methanol to afford 2-bromo-4,5-dimethoxybenzaldehyde (B1).
5) Compound B1 is demethylated in concentrated sulfuric acid to give 2-bromo-5-hydroxy-4-methoxybenzaldehyde (B2).
6. B2 is benzylated with benzyl bromide and potassium carbonate in DMF to obtain 5-benzyloxy-2-bromo-4-methoxybenzaldehyde (B3).
7) Compound B3 is oxidized with sodium chlorite and sulfamic acid in isopropanol to give acid B4.
8) Compound B4 is reacted with thionyl chloride in dichloromethane to give its corresponding acid chloride which is coupled with A3 in the presence of 3 N NaOH in dichloromethane to formamide C1.
9) Compound C1 is debenzylated with ethanolic hydrobromic acid to give desired product C2.
The synthesis of C2 as shown in Scheme I takes a number of steps and results in relatively low and inconsistent yields of the desired product. The removal of both benzyl ether protecting groups by hydrobromic acid gives a major impurity C3 (formula shown below) resulting from benzyl migration to the phenol ring. This impurity proves to be very difficult to remove from the product.

Therefore, there is a need for the development of a process for the preparation of N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5 hydroxy-4-methoxy benzene carboxamide (C2) via a simple, short, relatively inexpensive and highly efficient synthesis.